Biological resonance: matching internal timing to environmental fluctuations

在几乎所有的生物体中，固有的计时系统（生物钟）在一天中协调生理和行为的节奏模式。这些定时器还能响应外部环境的提示，如光照周期和食物供应。在哺乳动物中，昼夜节律调节我们的日常行为模式（我们何时睡觉，睡多久，何时吃饭），以及支持这种行为的潜在生理学（例如体温，激素释放和肝功能的节律）。不幸的是，现在似乎很清楚，现代社会的24小时生活方式（轮班工作，睡眠限制，破坏饮食模式）对我们身体“自然”节奏的破坏与代谢疾病（肥胖，糖尿病）有关。因此，我们必须了解内部计时器如何将我们的生理机能与环境相协调，以及当这种协调被破坏时会产生什么样的后果。直到最近，人们才相信哺乳动物的昼夜节律完全由大脑的一个小区域决定，即视交叉上核（SCN）。我们现在知道这不是真的，时钟存在于大脑的许多区域和几乎所有的外围器官中。在每个组织中，许多功能都是由当地的钟表机构控制的，例如肝脏葡萄糖生产的每日节律。这些外周组织时钟受到有节奏的进食活动（通常由SCN支配）的强烈影响，因此受到有节奏的能量通量的影响。因此，当进食不遵循SCN驱动的节律时，许多行为和生理过程可以与SCN分离。这可以很容易地在实验室老鼠身上模拟，使用限制的喂养时间表，迫使这些夜间动物在白天进食。为了了解我们的生理机能，特别是我们保持能量平衡的能力，是如何受到干扰的活动或喂养模式的影响，我们将研究当外部环境与大脑和肝脏的内部时钟相反时会发生什么，或者当身体中的不同时钟不能彼此保持同步时。这在肝脏等组织中尤其重要，因为肝脏必须科普能量供应的大幅波动（由于进食/禁食周期）。我们将使用转基因小鼠，其中我们改变了所有组织或选择性SCN或肝脏中的时钟速度（每个周期20小时与24小时）。我们的目的不是停止或消除小鼠体内的生物钟（也不是在它们的任何组织系统中），而是揭示当我们以不同的速度或阶段运行这些生物钟时对能量代谢的影响。这更接近于真实的世界。我们还将挑战这些小鼠的高脂肪饮食，以确定它们科普能量摄入大幅变化的能力。这可能与真实的世界特别相关，在现实世界中，人们经常在不适当的时间（如睡前）吃大量的高热量食物。迄今为止，测量特定组织的节律反应非常困难。然而，我们将使用一种令人兴奋的新方法来跟踪自由移动小鼠的肝脏振荡。这是通过注射一种含有发光基因的病毒来实现的，该基因会响应特定代谢途径的激活而振荡。因此，我们可以跟踪肝脏的核心时钟如何响应改变的进食时间表，甚至可以跟踪调节葡萄糖产生、脂肪酸合成或蛋白质代谢的代谢基因如何改变其表达。我们相信，这项非凡的新技术将大大增加对肝脏等组织如何响应环境线索的理解，并具有广泛的应用，并且还可能导致减少动物使用，因为现在可以从一只动物身上获得比以前更多的信息。

In virtually all organisms, inherent timing systems (circadian clocks) orchestrate rhythmic patterns of physiology and behaviour across the day. These timers are also responsive to external environmental cues, such as cycles in light and food availability. In mammals, the circadian clockwork regulates our daily patterns of behaviour (when and how long we sleep, when we eat), and also the underlying physiologies that support such behaviour (e.g. rhythms in body temperature, hormone release and liver function). Unfortunately, it now seems clear that disruption of our bodies' 'natural' rhythms by modern societies' 24h lifestyle (shift work, sleep restriction, disrupted eating patterns) is associated with metabolic disease (obesity, diabetes). Therefore, it is critical that we understand the basic biology behind how internal timers align our physiology to the environment and what the consequences are when that alignment is disrupted.Until recently, it was believed that circadian timing in mammals was determined wholly by a small area of the brain, the suprachiasmatic nucleus (SCN). We now know this not to be true, and that clocks reside in many areas of the brain and virtually all peripheral organs. Within each tissue, many functions are controlled by the local clockwork, such as daily rhythms in liver glucose production. These peripheral tissue clocks are strongly influenced by rhythmic feeding activity (normally governed by the SCN) and hence rhythmic energy flux. As a consequence, many behavioural and physiological processes can be decoupled from the SCN when feeding does not adhere to an SCN driven rhythm. This can be modelled easily in laboratory mice using restricted feeding schedules, which force these nocturnal animals to eat in the day.To understand how our physiology, and especially our ability to maintain energy balance, is affected by disrupted activity or feeding patterns, we will examine what happens when the external environment is put in opposition to internal clocks in the brain and liver, or when different clocks in the body are not able to keep in time with one another. This is especially important in tissues such as the liver, which must cope with large fluctuations in energy supply (due to feeding/fasting cycles). We will use genetically modified mice in which we have changed the speed of the clock (20h vs 24h per cycle) in all tissues or selectively in either the SCN or the liver. Our aim is not to stop or remove the clock within the mice (nor in any of their tissue systems), but reveal the consequences to energy metabolism when we run these clocks at different rates or phases to the external environment (light and meal times). This is much closer to the real world. We will also challenge these mice will high fat diet to determine their ability to cope with vastly altered energy intake. This may be particularly relevant to the real world, where large high calorie meals are often eaten at inappropriate times (such as before bed). To date, it has been very hard to measure rhythmic responses in a particular tissue. However, we will use an exciting new method to track liver oscillations in free-moving mice. This is achieved by injecting a virus containing a light-emitting gene, which oscillates in response to activation of a specific metabolic pathway. Thus, we can track how the core clockwork of the liver responds to altered feeding schedules, or even of how metabolic genes regulating glucose production, fatty acid synthesis or protein metabolism change their expression. We are confident that this remarkable new technology will greatly increase understanding of how tissues such as liver respond to environmental cues, and be of wide-spread application, and also potentially lead to reduced animal usage as greatly more information can now be obtained from one animal than before.